tbuckley/cabot-search huggingface dataset:
Abstract LB159: Deregulation of CTC-associated RPL/RPS protein expression inhibits melanoma brain metastasis
Authors: Tetiana Yuriyivna Bowley, Seth Merkley, Irina Lagutina, Dario Marchetti
Journal: Cancer Research (2023)

Abstract Melanoma brain metastasis (MBM) is associated with poor prognosis and low survival rates. MBM is diagnosed clinically in up to 60% of melanoma patients and in up to 80% of patients at autopsy. Circulating Tumor Cells (CTCs) are “seeds” of fatal metastasis and the smallest functional units of cancer. Our previous studies have employed a multilevel approach to identify a common CTC signature for ribosomal protein large/small subunits (RPL/RPS) which is linked to MBM development and progression1. Here, we hypothesized that targeting ribosomal biogenesis prevents MBM onset in CTC-derived xenografts. First, we treated CTC-injected MBM mice with RPL15 inhibitor omacetaxine to monitor metastatic progression. Second, parallel cohorts of mice were treated with CDK4/CDK6 inhibitor palbociclib with or without omacetaxine to assess effects of cell proliferation. Total flux of MBM signal was measured by IVIS and found to be higher in untreated mice. Mouse necropsies revealed decreased levels of MBM, along with metastatic dissemination to other organs. Third, collected mouse blood was analyzed by the FDA-approved ParsortixTM platform to enumerate CTC/CTC clusters (IHC), and evaluate their gene expression (RNA-seq). Lastly, metabolic profiling of inhibitor-treated versus untreated MBM CTC-derived clones was performed in vitro. Collectively, our findings indicate that the deregulation of ribosomal proteins inhibits MBM progression. This implicates a specific vulnerability of aggressive CTC subsets with high RPL/RPS content in MBM patients. RPL/RPS genetic screening could be a prognostic indicator of MBM severity and clinical outcomes. Our work promotes the concept that therapies targeting RPL/RPS proteins merit exploration as potential suppressors of metastatic progression in general, MBM in particular. 1. Bowley T, Lagutina I, Francis C, Sivakumar S, Selwyn R, Taylor E, et al. The RPL/RPS gene signature of melanoma updates CTCs associates with brain metastasis. Cancer Research Communications 2022;2: 1445-57. Citation Format: Tetiana Yuriyivna Bowley, Seth Merkley, Irina Lagutina, Dario Marchetti. Deregulation of CTC-associated RPL/RPS protein expression inhibits melanoma brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB159.
Abstract LB352: KRAS inhibition enhances immunogenicity of KRASG12C colorectal cancer
Authors: Jun Tian, Ferran Fece de la Cruz, Kelly Burke, Tomonori Oka, Jacquelyn M. Curtis, Princy Sindurakar, Edmond Wong, Shadmehr Demehri, Arlene Sharpe, Ryan Corcoran
Journal: Cancer Research (2023)

Abstract RAS mutations are the most common oncogenic mutations, present in &amp;gt;20% of human cancers. KRAS, the predominantly mutated isoform of RAS, is mutated in 40% of colorectal cancer (CRC), leading to constitutive activation of the MAPK (RAS/RAF) pathway and other downstream effectors. Due to the difficulty of targeting RAS, the first KRASG12C selective inhibitor has only been developed recently and approved by the FDA for non-small cell lung cancer. However, the inhibitor demonstrated much lower response rates in CRC (&amp;lt;20%) than other cancer types. Thus, developing effective therapies for KRAS mutant (KRASm) CRC still remains challenging. Oncogenic KRAS signaling has been shown to have immunosuppressive effects on tumor microenvironment, thus we hypothesized that KRAS inhibitor can indirectly enhance antitumor immunity, providing a rationale for their combination with immune checkpoint blockade. Indeed, using a syngeneic KRASG12C CRC mouse model with knockout of APC, TP53, SMAD4 and expressing KRASG12C, we observed significant increase in the percentage of CD3+CD8+ T cells as well as changes in myeloid populations in tumors treated with KRASG12C inhibitor compared with vehicle control. Combination of KRASG12C/PD-1 inhibition produced a more substantial and sustained reduction in tumor growth compared with KRAS or PD-1 inhibition alone. KRASG12C CRC mouse model represents a proper tool to study tumor cell-intrinsic mechanism of cooperativity between KRAS inhibition and immune response, since KRASG12C inhibitor targets KRASm tumor cells only without having direct effects on stromal and immune cells. Interestingly, we found tumor-intrinsic immune programs induction by KRAS/MAPK inhibition in KRASG12C CRC mouse models and patient-derived organoid models. We also found that KRASG12C inhibition upregulates T-cell recruiting chemokines CXCL9 and CXCL10 via IRF1 in KRASm tumor cells, which might be one of the potential mechanisms underlying enhanced infiltration of CD3+CD8+ T cells. These data suggest a link between KRAS inhibition and anti-tumor immunity, thus provide insights into novel combination strategies for KRASG12C colorectal cancers. Citation Format: Jun Tian, Ferran Fece de la Cruz, Kelly Burke, Tomonori Oka, Jacquelyn M. Curtis, Princy Sindurakar, Edmond Wong, Shadmehr Demehri, Arlene Sharpe, Ryan Corcoran. KRAS inhibition enhances immunogenicity of KRASG12C colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB352.
Abstract LB087: IFN-gamma targets tumor vascular endothelial cells, causing impaired perfusion and tumor growth suppression in adoptive T cell therapy
Authors: Qiaoya Lin, Colleen Olkowski, Peter L. Choyke, Noriko Sato
Journal: Cancer Research (2023)

Abstract CD8 T cell-secreted interferon-gamma (IFNγ) is a key factor in controlling adoptive T cell therapy (ACT) outcome. However, IFNγ effects on non-tumor cells (e.g., stroma and blood vessels) that could indirectly impact the therapy are not well characterized. We aim to dissect the spatiotemporal effects of IFNγ in the tumor microenvironment in ACT and the underlying mechanism of the therapy. An ACT using ex vivo-activated ovalbumin (OVA)-specific OT-1 T cells suppressed the growth of MCA-205-OVA-GFP fibrosarcoma or MOC2-SIINFEKL oral squamous cell carcinoma in wild-type mice. However, in IFNγR1-deficient hosts, the ACT failed, indicating that non-tumor cells were crucial targets of IFNγ. Furthermore, the efficacy was also abrogated in bone-marrow chimeras generated by transferring the wild-type bone-marrow to lethally irradiated Tie2-Cre-Ifngr1flox/flox mice. As IFNgR1 expression is specifically deficient in endothelial cells in these chimeras, this result indicates that IFNγ action on endothelial cells is indispensable for ACT. Early after T cell transfer (1.5 days), the fraction of OT-1 T cells infiltrating the tumor was small (0.098% of CD45+ cells) but produced high IFNγ (36.3%), resulting in the peak IFNγ concentration (47.3 pg/ml) in the whole tumor tissue in a 7-day observation period. In contrast, the highest accumulation of OT-1 T cells with low IFNγ production (2.9%) was observed on Day 4.5. Intravital imaging revealed that at Day 1.5, IFN-γ-RES-YFP-OT-1 T cells with a high level of IFNγ secretion (strong YFP+ signal) localized mainly along the tumor vessels. While more OT-1 T cells were observed in the MCA-205-OVA-GFP tumor tissue near the blood vessels on Day 4.5 than on Day 1.5, their IFNγ secretion was minimal. Degeneration of endothelial cells was observed via electron microscopy 3-4.5 days after T cells transfer. Consistent with this finding, CD31+ endothelial cell density decreased on Day 4.5 compared to Day 1.5 and significantly reduced blood perfusion in the entire tumor as observed by near-infrared imaging after IR800-albumin infusion. H&amp;E staining of tumor sections showed tumor necrosis on Day 4-7. In summary, our study demonstrates that endothelial cell targeting of CD8 T cell-derived IFNγ is critical for tumor suppression in ACT, impairing blood perfusion. These results provide novel insights into the mechanism of ACT. Citation Format: Qiaoya Lin, Colleen Olkowski, Peter L. Choyke, Noriko Sato. IFN-gamma targets tumor vascular endothelial cells, causing impaired perfusion and tumor growth suppression in adoptive T cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB087.
Abstract LB043: Pharmacological inhibition of ubiquitination sensitizes to DNA damaging agents by preventing homologous recombination repair
Authors: Sharad Awasthi, S. Stephen Yi, Daniel J. McGrail, Nidhi Sahni
Journal: Cancer Research (2023)

Abstract Therapies inducing DNA damage have been the backbone of cancer treatment for decades, but they often cause significant adverse effects reducing quality of life. Recently, inhibition of poly-ADP-ribose polymerase (PARP) has been shown to target tumor cells with deficient DNA homologous recombination (HR) double-strand break repair by converting single-strand DNA breaks into toxic double-strand breaks that cannot be resolved. This approach has been advantageous as healthy cells with functional HR repair are less effective, resulting in a more tolerable treatment. However, most cancers will not respond to PARP inhibition. Here, using a genome-wide CRISPR knockout functional genomics screen we identified that depletion of ubiquitination enzymes induced sensitivity to PARP inhibition in HR proficient ovarian cancer cells, as well as KRAS-mutant colorectal cancer cells which are generally resistant to PARP and other DNA damaging agents. Validation studies across multiple cancer lineages using cell line and organoid models confirmed that either silencing or pharmacological inhibition of ubiquitin-activating enzyme E1 (UBA1), which is required for ubiquitination, sensitized to PARP inhibition and other DNA damaging therapies. In vivo testing of combination PARP and UBA1 inhibition was well tolerated, and significantly extended survival of patient-derived xenografts compared to either therapy alone. Mechanistically, we found that UBA1 inhibition not only blocked HR repair to sensitize to PARP inhibition, but it also induced global increases in PARylation, which was subsequently inhibited by PARP inhibition. Taken together, these results demonstrate that inhibition of UBA1 sensitizes to PARP via multiple pathways, and the combination is well tolerated making it an ideal strategy to expand the therapeutic benefit of PARP inhibition. Citation Format: Sharad Awasthi, S. Stephen Yi, Daniel J. McGrail, Nidhi Sahni. Pharmacological inhibition of ubiquitination sensitizes to DNA damaging agents by preventing homologous recombination repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB043.
Abstract LB224: STC-1010 a new therapeutic vaccine promotes tumor cell death
Authors: Alban Bessede, George Alzeeb, Corinne Tortorelli, Jean-Philippe Guegan, Christophe Rey, Lionel Chalus, Benoit Pinteur, Paul Bravetti, Antoine Italiano
Journal: Cancer Research (2023)

Abstract BACKGROUND Colorectal cancer (CRC) is the third most commonly diagnosed cancer (10% of new cases in 2020) and the second leading cause of cancer-related death (9.4%) worldwide. CRC is often detected at late stages, with 38% of metastasis cases at diagnosis. This makes the development of efficient treatments crucial. Recent tremendous progress sets immunotherapy as a treatment option and opens multiple ways to address therapeutic challenges in CRC. Accordingly, we have previously developed therapeutic cancer vaccine based on stimulated tumor cells (STC) technology, that have already shown efficacy in immunocompetent mouse models. Same strategy was used in this study to generate the STC-1010 therapeutic vaccine, a novel human therapeutic CRC vaccine derivate from 3 human CRC cell lines, HCT116, HT29 and LOVO exposed to irradiation, heat shock, chemotherapy agents and haptenized. METHODS We evaluate STC-1010 for its potential to favor an immune stimulatory response on human monocytes-derived dendritic cells (moDCs) from 2 different donors through i) a derived Mixed Lymphocyte Reaction (dMLR) assay, ii) the assessment of their cytokine profile, iii) the evaluation of their capacity to activate autologous CD8+ T cells and finally iv) to promote apoptosis of three CRC cell lines (HCT116, HT29 and LS-174T). RESULTS We showed that STC-1010 induced IL-8 and IL-12 production, and reduced IL-10 during moDCs maturation. In addition, dendritic cells (DCs) exposed to STC-1010 during the maturation enhanced Interferon gamma (IFNg) production by CD8+ T cells (p=0,06 for donor 1 and p=0,0004 for donor 2) and amplified their anti-tumor activity, in combination with LPS/IFNg and CD40L. CD8+ T cells primed with STC-1010-treated DCs promote massive apoptosis of HCT116 and HT29 cells compared to the condition without STC-1010 (p&amp;lt;0,001 for all donors). The benefit of STC-1010 was not detectable with LS174T cells characterized by a low expression of HLA-ABC and used as negative control in this study. CONCLUSION Taken together, our results showed that Brenus STC-1010 human vaccine is an efficient strategy to educate immune system and promote the CRC cells death in vitro lending further support in favor of STC technology based on physical or chemical stimulation and haptenization to generate human cancer therapeutic vaccine. Citation Format: Alban Bessede, George Alzeeb, Corinne Tortorelli, Jean-Philippe Guegan, Christophe Rey, Lionel Chalus, Benoit Pinteur, Paul Bravetti, Antoine Italiano. STC-1010 a new therapeutic vaccine promotes tumor cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB224.
Abstract LB220: S095029: a novel clinical-stage Fc-silenced NKG2A-blocking antibody with best-in-class potential
Authors: Maria Melander, Bruno Laugel
Journal: Cancer Research (2023)

Abstract NKG2A and its ligand HLA-E are increasingly recognized as an important immune checkpoint restraining multiple lymphocyte populations involved in cancer immunity. Initially described as an NK cell inhibitory receptor, NKG2A’s role in regulating T-cell functions has recently come to the fore and is increasingly viewed as a key component of its immune suppressive functions. In addition, clinical studies have also provided proof-of-concept evidence for the superiority of dual NKG2A/PD-L1 blockade over anti-PD-L1 monotherapy. As of now clinical safety and efficacy results are only available for a single NKG2A-blocking antibody. This is in contrast with other immune checkpoint receptors (e.g., PD-1) where multiple blocking agents with different pharmacological properties have been assessed in the clinic, thereby providing a broad assessment of the target therapeutic potential and benefit to patients. Here, we report the generation and preclinical characterization of a novel monoclonal antibody (mAb) disrupting the NKG2A/HLA-E interaction. The Fc-attenuated IgG1 mAb S095029 binds NKG2A with a nM-range affinity and reverses the inhibitory effects of the NKG2A/HLA-E interaction in several experimental models, both in vitro and in vivo. As a single agent S095029 enhanced the killing activity and cytokine secretion of NK and γδ T-cells in co-culture with cancer cell lines of multiple tissue origins. We also show that S095029 increased the antibody-dependent cellular cytotoxicity (ADCC) mediated by Fc-competent mAbs in different antigen systems with high HLA-E expression. Of note, these immune-activating properties of S095029 compared favorably in benchmarking experiments with other clinical-stage anti-NKG2A mAbs. Finally, S095029 combination with PD-1 blocking agents, with or without an additional ADCC mAb component, conferred superior anti-tumor activity compared to treatments without NKG2A blockade. Overall, our in vitro and in vivo data support the clinical development of S095029 in tumor settings with adequate HLA-E expression and suggest potential differentiating characteristics compared to other anti-NKG2A mAbs. S095029 is currently being evaluated in phase 1 dose escalation studies as a single agent or in combination with anti-PD-1 therapy (NCT05162755). Citation Format: Maria Melander, Bruno Laugel. S095029: a novel clinical-stage Fc-silenced NKG2A-blocking antibody with best-in-class potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB220.
Abstract LB021: KN-052, a novel PDL1/OX40 bispecific antibody, exhibits potent antitumor efficacy
Authors: Ting Xu, Pilin Wang, Yang-Xin Fu, Kangping Guo, Jianjian Peng
Journal: Cancer Research (2023)

Abstract KN052 is a recombinant PDL1/OX40 bispecific antibody which can block PDL1 and PD1/CD80 pathway and active the OX40 signal pathway at the same time. Inhibited PDL1 can block cancer cells to evade T-cell-mediated immune responses and restores T-cell activation and antitumor responses. On the other hand, biding to OX40 which normally expressed on Treg cells can induce ADCC effect and kill the Treg cells. There is a synergistic effect between the blocking of PDL1 pathway and the activation of OX40 signal pathway in cell base assay. PBMCs from four healthy donors showed significant T cell activation effect under the stimulation of superantigen SEB, and the activity of PBMCs from three healthy donors was significantly stronger than that of two single target control antibodies alone and in combination. The anti-tumor activity of KN052 was evaluated by using hPD-L1/hOX40 humanized mouse with MC38 MCA205 syngeneic model. Significant anti-tumor effects were observed in both models in a dose-dependent manner. The HNSTD (highest non-severely toxic dose) of KN052 was determined as 30mg/kg in cynomolgus monkeys. These preclinical data demonstrated acceptable PK and safety profile of KN052 and indicated its potential in a variety of tumors. Citation Format: Ting Xu, Pilin Wang, Yang-Xin Fu, Kangping Guo, Jianjian Peng. KN-052, a novel PDL1/OX40 bispecific antibody, exhibits potent antitumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB021.
Abstract LB090: IL-18 secreting chimeric antigen receptor T cells targeting glypican-3show superior persistence and antitumor immunity against hepatocellular carcinoma
Authors: Joseph H. Jeong, Young-Kyun Chang, You-Yeon Kang, Jeong-Yun Lee, Sae-Rom Lee, Yun-Kyung Lee, Young-Ho Kim, Byoung S. Kwon
Journal: Cancer Research (2023)

Abstract Over the last decade, immunotherapy has revolutionized the way we treat cancer primarily by boosting the body’s own immune system to help fight cancer. In particular, an engineered T cell therapy, namely chimeric antigen receptor (CAR) T cell therapy, is a more aggressive way to modify T cells to recognize cancer cells and destroy them. Although these CAR-T therapies have shown remarkable clinical responses in patients with hematological malignancies, their efficacy in solid tumor treatment has been disappointing due to many challenges: lack of tumor-specific antigen targets, loss of the CAR T-cell persistence, the inability of CAR-T cells to effectively infiltrate into solid tumors, toxicities of cytokine release syndrome and neurologic toxicity, and the immunosuppressive tumor microenvironment (TME). In this regard, we report here that we have successfully developed a CAR-T cell therapy, referred to as EU307, to treat one type of solid tumor, hepatocellular carcinoma (HCC). EU307 is a fourth-generation CAR-T therapy that targets the HCC-specific tumor antigen of glypican-3 (GPC3), and also secretes IL-18 which results in autocrine co-stimulation of CAR-T cells and reprogramming of the TME into a tumor-killing environment. Through a sophistically optimized manufacturing process in our good manufacturing practices (GMP) facility, we are able to manufacture CAR-T cells with stem cell memory (TSCM) and central memory (TCM) phenotypes. Functionally, EU307, when infused with as little as 0.1 × 106 total cells per animal, showed superior in vivo persistence and antitumor immunity in an HCC tumor-bearing mouse model. Furthermore, a single dose toxicity study in the same disease mouse model determined the no observed adverse effect level (NOAEL) as 5.0 × 105 total cells per male and 1.0 × 106 total cells per female. Taken together, our studies demonstrate that we have a developed a novel fourth-generation CAR-T therapy to treat HCC, a solid tumor that expresses a high-level of tumor-specific GPC3, by overcoming previously limiting factors in the development of CAR-T therapies against solid tumors. Citation Format: Joseph H. Jeong, Young-Kyun Chang, You-Yeon Kang, Jeong-Yun Lee, Sae-Rom Lee, Yun-Kyung Lee, Young-Ho Kim, Byoung S. Kwon. IL-18 secreting chimeric antigen receptor T cells targeting glypican-3show superior persistence and antitumor immunity against hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB090.